ES2344920T3 - PHARMACEUTICAL COMPOSITION FOR THE TREATMENT OF PATHOLOGIES CAUSED BY THE GENERAL RESPONSE OF THE IMMUTARY SYSTEM. - Google Patents

Abstract

The present invention relates to a pharmaceutical composition consisting of amides of mono- and dicarboxylic acids and hydroxystilbenes, and may be used for the treatment of pathologies caused, sustained and/or characterised by an abnormal general response of the immune system, in both humans and animals.

Description

Pharmaceutical composition for the treatment of pathologies caused by the general response of the system immune

The present invention relates to a pharmaceutical composition comprising amides of mono acids and dicarboxylic and hydroxystilbenes for the treatment of pathologies caused, sustained and / or characterized by a general abnormal response of the immune system, both in beings Humans as animals.

State of the art

The bibliography is full of evidence of direct "interference" between the cell population that consists  in mast cells (M) and the general population of activated T lymphocytes (ATL).

The first evidence of the interaction between M and ATL cells began to emerge in the late 1990s, from an Israelite research group in immunology. In an interesting publication, the authors conclude by hypothesizing that the "T-mast cell" interaction can be bidirectional and represent an important regulatory and / or modulating phase of the general immune response (Mekori YA et al . J. Allergy Clin. Immunol September 1999; 104: 517-23). In 2002 a direct interaction between the two cell lineages was first shown; Mast cell mediators that originate from human M cell degranulation can increase interferon-y production by CD8 + and CD4 + T lymphocytes (Francina L. de Pater-Huijsen et al . - Immunology May 2002; 106: 11-19 ). This fascinating hypothesis, reiterated in a "review" published in Nature Immunology in February 2005 (Galli S. et al . - Nature Immunology February 2005; 6 (2): 135-42), is confirmed in the literature in April 2005 when the same group, to which Stephen Galli belongs, shows the importance of degranulated TNF from M cells over the activation of T lymphocytes (Nakae S. et al . - Proc. Natl. Acad. Sci. USA April 2005; 102 (18): 6467-72); The authors conclude by claiming the identification of a multiple mechanism through which mast cells can influence the proliferation and production of cytokines from T lymphocytes. Direct "interference" between mast cells and T lymphocytes was only clearly confirmed and discussed in October. 2005 (Salamon P. et al . - Allergy October 2005; 60 (10): 1316-9) and its role in inflammatory processes mediated by T lymphocytes was demonstrated.

Currently, diseases characterized by an abnormal immune response is treated by administration of appropriate drugs that exclusively modulate the lymphocyte activity

The possibility of modulating the response general immune modulating simultaneously the mast cells and Activated T lymphocytes have never been proposed or described.

Therefore, the underlying idea behind the The present invention is to modulate the general immune response  of the organism simultaneously modulating the reactivity of the mast cells (M) (understood as the degranulation response differential thereof) and the functional response and to cytokines of activated T lymphocytes (ATL).

Said simultaneous modulation can be obtained at through the use of a pharmaceutical composition as described in claim 1.

Therefore, the present invention relates to a pharmaceutical composition comprising amides of mono acids and dicarboxylic and polyphenols that belong to the family of hydroxystilbenes, and that can be used for the treatment of provoked, sustained and / or immunoinflammatory diseases characterized by abnormal general immune responses, both in humans and animals.

In particular, such diseases are the caused by exogenous antigenic stimuli (those called "non-self" stimuli). These include allergic rhinitis, bronchial asthma, allergic alveolitis, urticaria, atopic dermatitis, contact dermatitis, conjunctivitis and anaphylaxis. Approximately 10% of the world's population suffers from allergic disorders, with a global dominance in industrialized countries, with 15% peaks in subpopulations (atopic dermatitis of the infant).

Other types of disorders include caused by endogenous antigenic stimuli (the so-called "own" stimuli), usually defined as disorders autoimmune, characterized by hypersensitivity to organism components These include multiple sclerosis, psoriasis, bullous pemphigus, pigmented urticaria, scleroderma systemic, uveitis, scarring eye pemphigus, rheumatoid arthritis, Systemic lupus erythematosus and psoriatic arthritis. The diseases autoimmune observed most often affect not less than 5% of the world population.

Disorders characterized and / or sustained by neuroimmunogenic inflammation (in practice almost all inflammatory diseases) are specific disorders of organs such as interstitial cystitis in humans and cats, prostatitis, osteoarthritis in humans and dogs, numerous Autonomic and somatic neuropathies, vulvovaginitis, vestibulitis vulvar, viral infections of the vagina and cervix, oral mucositis, Crohn's disease, ulcerative colitis, dermatitis geriatric (characterized by a characteristic symptomatology such such as dryness, dyskeratosis, itching, epidermal lesions, etc.), radiation dermatitis (from the sun, radiation therapy in patients with cancer, etc.) and many others. Epidemiological estimates they consider that the incidence of such diseases is not lower to 40% of the population, and that increases rapidly due to the increase of the overall life time on average and, in the medical field veterinary, considering the increasing attention paid to domestic animals. The pharmaceutical composition of the invention comprises one or more of the derivatives of N-acylethanolamine selected from N-palmitoylethanolamine, N- (2-hydroxyethyl) -lauroylamide, N, N'-bis (2-hydroxyethyl) nonandiamide, N, N'-bis (2-hydroxyethyl) -2-dodecendiamide, N, N-bis (2-hydroxyethyl) -lauroylamide  and one or more of the hydroxystilbenes selected from Resveratrol and resveratrol glycosides. Hydroxystilbenes they can be in both trans and cis isomeric forms.

The synthesis of derivatives of N-acylethanolamine and hydroxystilbenes of the invention is well known in the art and is shown by way of for example, in EP 0 550 006, in the application US2004 / 0014682A1, in US document 5,506,224, in US 5,618,842, in EP 0 751 947 and in EP 1 115 392.

One or more derivatives of N-acylethanolamine and the one or more hydroxystilbenes are comprised within the composition, respectively, in amounts ranging from 0.0001 mg / kg / day to 20 mg / kg / day, preferably from 0.05 mg / kg / day to 10 mg / kg / day for N-acilderivated amino alcohols, and preferably from 0.005 mg / kg / day to 10 mg / kg / day for hydroxystilbenes

These active ingredients, optionally micronized or micronized together with one or more excipients properly mixed, they can be formulated for administration oral, buccal, parenteral, rectal, transdermal or topical, or in a form adapted for administration by inhalation or insufflation (either through the mouth or nose).

These active ingredients mixed in a manner appropriate can be formulated for oral, oral administration, parenteral, rectal, transdermal, topical on the skin and mucosa, or in a form adapted for administration by inhalation or insufflation (either through the mouth or nose).

Pharmaceutical compositions for oral administration may be, for example, in the form of tablets or capsules (containing powders or mixtures in oil), acceptable excipients such as binding agents (for example pregelatinized corn starch, polyvinylpyrrolidone or carboxymethyl cellulose); fillers (eg lactose, cellulose microcrystalline or calcium hydrogen phosphate); lubricants (for example magnesium stearate, talc or silica); disintegrating (by example potato starch or sodium starch glycolate); or surfactants (for example sodium lauryl sulfate). The tablets they can be coated using methods well known in the art. The Liquid preparations for oral administration may be, by example, in the form of solutions, syrups or suspensions or may be as freeze-dried products that must be reconstituted before its use, with water or other suitable vehicles. Such preparations liquids can be obtained using conventional methods with pharmaceutically acceptable additives such as suspension (for example sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifiers (for example lecithin or gum arabic); non-aqueous vehicles (eg oil of almond, oily esters, ethyl alcohol or vegetable oils fractionated); and preservatives (for example methyl or propyl or acid p-hydroxybenzoates sorbic). The preparations may also contain appropriate flavorings, dyes, sweeteners and preservatives

Preparations for oral administration can be formulated appropriately to allow release controlled of the active substance.

Compositions for oral administration they can be in the form of lozenges or tablets Conventionally formulated.

The active ingredients mixed in a way appropriate can be formulated for parenteral administration by injection. Formulations for injections can be presented in an individual pharmaceutical form, for example in ampoules with preservative added. The compositions can be presented in the form mentioned above as suspensions, solutions or emulsions in aqueous or oily vehicles and may contain agents of formulation such as suspending agents, stabilizers and / or dispersants. Alternatively, the active substance may be in powder form for reconstitution, before use, using a appropriate vehicle, for example sterile water.

According to the present invention, the principles assets can also be formulated in rectal compositions such as suppositories or retention enemas, which contain for example components of common basic suppositories such as butter cocoa or other glycerides.

In addition to the compositions described previously, the compounds can also be formulated as slow release preparations. Such preparations of action prolonged can be administered as implants (for example, via subcutaneously, transcutaneously or intramuscularly) or by intramuscular injection. Therefore, for example, the principles assets can be formulated with hydrophobic or polymeric materials suitable (for example in the form of an emulsion in an oil suitable) or an ion exchange resin or as little derivatives soluble, for example as a slightly soluble salt.

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The formulated pharmaceutical compositions of appropriate manner of the invention can be administered to dosages varying between 0.1 and 30 mg / kg, 1 to 4 times at day. The dosage of the compositions will be determined according to the disease to be treated, the level of severity of said disease and the patient's condition. In addition, the dose will depend on the selected administration route. It should be considered that it can it is necessary to make continuous adjustments to the dosage depending of the patient's age and weight, in addition to the severity of the clinical condition to be treated. The exact dose and route of administration will finally be at the discretion of the doctor or vet.

Experimental section

Here are some examples of Pharmaceutical formulations according to the invention.

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Example 1 Tablets for oral use

Each tablet contains:

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powder micronized together containing:

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N-palmitoylethanolamine 300 mg

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resveratrol 25 mg

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Resveratrol glycoside 10 mg

-

lactose 200 mg

-

100 mg corn starch

-

talcum powder 10 mg

-

magnesium stearate 5 mg

-

hydroxypropyl methylcellulose 5 mg

-

1.5 mg titanium dioxide

-

oxide yellow iron (E172) 0.4 mg

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Example 2 Capsules for oral use

Each soft gelatin capsule contains:

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N- (2-hydroxyethyl) -lauroylamide 150 mg

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Resveratrol glycoside 50 mg

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soy lecithin 30 mg

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oil vegetable 300 mg

-

Erythrosine (E127) 0.1 mg

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Example 3 Lyophilized ampoules

Each lyophilized ampoule contains:

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N, N'-bis- (2-hydroxyethyl) -nonandiamide 100 mg

-

Resveratrol glycoside 50 mg

-

100 mg mannitol

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Each solvent vial contains:

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Water 3 ml pyrogen-free double-distilled

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Example 4 Ampoules for intramuscular use

Each vial contains:

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N, N'-bis- (2-hydroxyethyl) -nonandiamide 50 mg

-

Resveratrol glycoside 50 mg

-

physiological solution (saline solution isotonic) as required up to 2 ml

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Example 5 Cream for dermatological use

100 g of cream contain:

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N, N'-bis- (2-hydroxyethyl) -nonandiamide 2 g

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0.5 g resveratrol

-

Resveratrol glycoside 0.3 g

-

sorbitan monostearate 0.5 g

-

monostearate polyoxyethylene sorbitan 4.5 g

-

ethyl alcohol 3.0 g

-

acid stearic 3.0 g

-

oil paraffin 10.0 g

-

70% sorbitol 6.0 g

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methyl p-oxybenzoate 0.2 g

-

propyl p-oxybenzoate 0.05 g

-

Water deionized as required up to 100.0 g

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Example 6 Gel for gynecological use

100 g of gel contain:

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N, N'-bis- (2-hydroxyethyl) -nonandiamide 1.0 g

-

Resveratrol glycoside 1.0 g

-

glycerin 8.0 g

-

Oil of hydrogenated castor 1.0 g

-

1.0 g propylene glycol

-

1.5 g polycarbophil

-

vitamin E acetate 0.5 g

-

vitamin A acetate 0.05 g

-

poly (vinyl alcohol) 0.2 g

-

acid hyaluronic 0.2 g

-

phytosphingosine 0.02 g

-

methyl p-oxybenzoate 0.10 g

-

2-phenylethanol 0.15 g

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quercetin 0.1 g

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Water as required up to 100.0 g

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Example 7 Soft gelatin vaginal suppositories

Each egg contains:

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N, N'-bis- (2-hydroxyethyl) -trans-2-dodecendiamide 0.5 g

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Resveratrol glycoside 0.6 g

-

propylene glycol 1.5 g

-

Erythrosine (E127) 0.1 mg

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Example 8 Ophthalmic ointment

100 g of ointment contain:

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N, N'-bis- (2-hydroxyethyl) -trans-2-dodecendiamide 0.5 g

-

0.5 g resveratrol

-

Viscose Vaseline as required up to 100.0 g

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Example 9 Sterile ophthalmic eye drops (in dose containers individual)

100 g of eye drops contain:

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N, N'-bis- (2-hydroxyethyl) -nonandiamide 0.5 g

-

Resveratrol glycoside 0.3 g

-

Salt hyaluronic acid sodium 0.01 g

-

pyrogen-free physiological solution as required up to 100.0 g

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Example 10 Rectal suppositories

Each suppository contains:

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N-palmitoylethanolamine 0.3 mg

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resveratrol 0.2 mg

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Resveratrol glycoside 0.05 mg

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fatty excipient for suppositories

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according up to 2.0 g required

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Example 11 Powder for use in podiatry

100 g of powder contain:

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Powder micronized together containing:

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N, N'-bis- (2-hydroxyethyl) -lauroylamide 2.3 g

-

1.5 g resveratrol

-

Resveratrol glycoside 0.8 g

-

attapulgite 50.0 g

-

3.0 g acrylic copolymer

-

vitamin E acetate 1.0 g

-

dimethicone 2.0 g

-

Isopropyl myristate 2.0 g

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menthol 1.5 g

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eucalyptol 0.5 g

-

micronized attapulgite as required up to 100.0 g

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Example 12 Solution against nail fall

100 g of solution contain:

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N, N'-bis- (2-hydroxyethyl) -nonandiamide 2.0 g

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N, N'-bis- (2-hydroxyethyl) -lauroylamide 1.0 g

-

Resveratrol glycoside 2.0 g

-

phytosphingosine 1.0 g

-

80.0 g isopropyl alcohol

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acetone 2.0 g

-

acid undecylenic 0.2 g

-

Vitamin A palmitate 0.5 g

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urea 3.0 g

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Water deionized as required up to 100.0 g.

Claims (7)

1. Pharmaceutical composition comprising one or more of N-acylethanolamine derivatives selected from N-palmitoylethanolamine, N- (2-hydroxyethyl) -lauroylamide, N, N'-bis (2-hydroxyethyl) nonandiamide, N, N'-bis (2-hydroxyethyl) -2-dodecendiamide, N, N-bis (2-hydroxyethyl) -lauroylamide and one or more of the hydroxystilbenes selected from resveratrol and resveratrol glycosides. 2. Composition according to claim 1, in the that resveratrol or resveratrol glycosides are isomers trans and cis isomers. 3. Composition according to claim 1 or 2, in which said one or more N-acylethanolamines is include in amounts ranging from 0.0001 mg / kg / day up to 20 mg / kg / day, preferably from 0.05 mg / kg / day to 10 mg / kg / day, and said one or more hydroxystilbenes are included in amounts that They range from 0.005 mg / kg / day to 10 mg / kg / day. 4. Pharmaceutical formulation comprising the composition according to claims 1 to 3, together with excipients pharmaceutically acceptable. 5. Formulation according to claim 4, for oral, oral, parenteral, rectal, transdermal, topical application on the skin and mucosa, for inhalation or insufflation. 6. Composition according to claims 1 to 3, For use as a medicine. 7. Use of the composition according to claims 1 to 3, for the preparation of a medicament for the treatment of diseases caused, sustained and / or characterized by the abnormal general response of the immune system in humans and animals, wherein said diseases they are caused by exogenous antigenic stimuli, preferably: allergic rhinitis, bronchial asthma, allergic alveolitis, urticaria, atopic dermatitis, contact dermatitis, conjunctivitis, anaphylaxis; diseases caused by endogenous antigenic stimuli (autoimmune diseases), preferably multiple sclerosis, psoriasis, bullous pemphigus, pigmented urticaria, systemic scleroderma, uveitis, scarring ocular pemphigus, rheumatoid arthritis, systemic lupus erythematosus, psoriatic arthritis; diseases characterized and / or sustained by neuroimmunogenic inflammation, preferably interstitial cystitis in humans and cats, prostatitis, osteoarthritis in humans and dogs, numerous autonomous and somatic neuropathies, vulvovaginitis, viral infections of the vagina and cervix, vulvar vestibulitis , oral mucositis, Crohn's disease, ulcerative colitis, geriatric dermatitis, dermatitis induced by radiation therapy or solar radiation.